Salts of 4-aniline quinazoline derivative

Abstract

The present invention relates to salt forms of N-{4-[3-chloro-4-(3-fluoro-benzyloxy)phenylamino]-quinazolin-6-yl}-acrylamide as exemplified by formula (I), methods of preparation thereof, pharmaceutical compositions comprising the same and their use thereof. The salt forms of the present invention, which possess excellent tumor inhibitory activity, good bioavailability and low toxicity in an animal body, are suitable for use of preparation of anti-tumor medicaments.

1. A pharmaceutically acceptable salt of the compound of formula (I): 
       
         
           
           
               
               
           
         
       
     
     
       2. The salt of  claim 1 , wherein the salt is an acid addition salt formed from the compound of formula (I) with an inorganic or organic acid, or a base addition salt formed from the compound of formula (I) with an inorganic or organic base. 
     
     
       3. The salt of  claim 2 , wherein the salt is an acid addition salt. 
     
     
       4. The salt of  claim 3 , wherein the acid addition salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, biphosphate, borate, acetate, oxalate, malonate, valerate, benzoate, p-toluenesulfonate, methanesulfonate, tartrate, lactate, benzoate, toluate, citrate, maleate, fumarate, malate, pamoate, salicylate, vanillate, mandelate and succinate. 
     
     
       5. The salt of  claim 4 , wherein the acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, carbonate, p-toluenesulfonate, methanesulfonate, benzoate, salicylate, oxalate, acetate, valerate, malonate and tartrate. 
     
     
       6. The salt of  claim 1 , wherein the salt is an acid addition salt and the acid addition salt is hydrochloride or p-toluenesulfonate. 
     
     
       7. The salt of  claim 2 , wherein the salt is a base addition salt. 
     
     
       8. The salt of  claim 7 , wherein the base addition salt is selected from the group consisting of alkali metal salt, alkali earth metal salt, quaternary ammonium cation salt and amine salt. 
     
     
       9. The salt of  claim 8 , wherein the base addition salt is selected from the group consisting of sodium salt, potassium salt, calcium salt, magnesium salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary ammonium salt, methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt and ethylamine salt. 
     
     
       10. The salt of  claim 9 , wherein the base addition salt is triethylamine salt. 
     
     
       11. A process for preparing the salt as defined in  claim 1  comprising the steps of:
 (a) dissolving the compound of formula (I) in an organic solvent, and adding dropwise an acid-containing solvent or a base-containing solvent with stirring; and 
 (b) filtering the resulting mixture directly or after concentrating, to obtain a solid; water-washing, and drying the solid to obtain the salt. 
 
     
     
       12. A process of  claim 11 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, ethyl acetate, tetrahydrofuran, triethylamine, diethyl ether, 1,4-dioxane and a combination thereof. 
     
     
       13. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of formula (I): 
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable carrier. 
     
     
       14. The pharmaceutical composition of  claim 13 , wherein the salt is an acid addition salt formed from the compound of formula (I) with an inorganic or organic acid, or a base addition salt formed from the compound of formula (I) with an inorganic or organic base. 
     
     
       15. The pharmaceutical composition of  claim 14 , wherein the salt is an acid addition salt. 
     
     
       16. The pharmaceutical composition of  claim 15 , wherein the acid addition salt is selected from the group consisting of hydrobromide, hydrochloride, sulfate, bisulfate, carbonate, bicarbonate, sulfite, phosphate, biphosphate, borate, acetate, oxalate, malonate, valerate, benzoate, p-toluenesulfonate, methanesulfonate, tartrate, lactate, benzoate, toluate, citrate, maleate, fumarate, malate, pamoate, salicylate, vanillate, mandelate and succinate. 
     
     
       17. The pharmaceutical composition of  claim 16 , wherein the acid addition salt is selected from the group consisting of hydrochloride, sulfate, phosphate, carbonate, p-toluenesulfonate, methanesulfonate, benzoate, salicylate, oxalate, acetate, valerate, malonate and tartrate. 
     
     
       18. The pharmaceutical composition of  claim 13 , wherein the salt is an acid addition salt and the acid addition salt is hydrochloride or p-toluenesulfonate. 
     
     
       19. The pharmaceutical composition of  claim 13 , wherein the salt is a base addition salt. 
     
     
       20. The pharmaceutical composition of  claim 19 , wherein the base addition salt is selected from the group consisting of alkali metal salt, alkali earth metal salt, quaternary ammonium cation salt and amine salt. 
     
     
       21. The pharmaceutical composition of  claim 20 , wherein the base addition salt is selected from the group consisting of sodium salt, potassium salt, calcium salt, magnesium salt, tetramethyl quaternary ammonium salt, tetraethyl quaternary ammonium salt, methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt and ethylamine salt. 
     
     
       22. The pharmaceutical composition of  claim 21 , wherein the base addition salt is triethylamine salt.